There is a significant unmet medical need for therapies to treat neurodegenerative disorders. Alzheimer's disease (AD) and Huntington's disease (HD), for example, have no cure or even an effective treatment. These two diseases alone cost the US healthcare system $100+ billion a year. SIRT1 is a member of the sirtuin family of NAD+-dependent deacetylases, which are thought to have evolved very early in life's history to enhance an organism's chances of surviving adversity and may underlie the neuroprotection and other health benefits provided by caloric restriction (CR). Hyperactivation of SIRT1 is responsible for the remarkable ability of neurons to survive long afer being cut in the case of the Wallerian mouse mutant (WldS). We and others have also found that SIRT1 protects neurons against death and dysfunction in models for HD, AD and ALS. Resveratrol (a SIRT1-activating molecule) or "STAC" can significantly delay neurodegeneration and cognitive decline in the p25-Tg mouse model of AD. Our lab has generated 20+ analogs of resveratrol, some of which have improved stability and potency. We have also generated the first SIRT1 tissue-specific inducible transgenic mouse. In this proposal, we will investigate the mechanism by which SIRT1 provides protection against neurodegeneration and test whether SIRT1 activation can delay the progression of different two neurodegenerative disorders, namely AD and HD using mouse genetic models. Preliminary experiments indicate that SIRT1 works by suppressing apoptosis and increasing DNA repair, the latter of which is emerging as a possible contributor to brain aging and a variety of neurodegenerative disorders. The STACs and SIRT1 transgenic animals we have generated place us in a unique position to be able to test these hypotheses. Lay description: Ten percent of Americans over the age of 65 suffer from Alzheimer's disease, a disease estimated to cost approximately $100 billion annually. The SIRT1 protein is considered by many to possibly be a master regulator of the body's innate defenses against disease and debilitation. SIRT1 is somehow able to keep neurons healthy and alive when they would otherwise die. We aim to uncover the mechanism by which S1RT1 protects neurons and to develop molecules that stimulate the SIRT1 protein and provide protection against a variety of neurodegenerative diseases.